Design and Synthesis of Novel Epigenetic Inhibitors Targeting Histone Deacetylases, DNA Methyltransferase 1, and Lysine Methyltransferase G9a with In Vivo Efficacy in Multiple Myeloma
Obdulia Rabal 1 , Edurne San José-Enériz 2 , Xabier Agirre 2 , Juan Antonio Sánchez-Arias 1 , Irene de Miguel 1 , Raquel Ordoñez 2 , Leire Garate 2 , Estíbaliz Miranda 2 , Elena Sáez 1 , Amaia Vilas-Zornoza 2 , Antonio Pineda-Lucena 1 , Ander Estella 1 , Feifei Zhang 3 , Wei Wu 3 , Musheng Xu 3 , Felipe Prosper 2 4 , Julen Oyarzabal 1
Concomitant inhibition of key epigenetic pathways involved in silencing tumor suppressor genes has been recognized as a promising strategy for cancer therapy. Herein, we report a first-in-class series of quinoline-based analogues that simultaneously inhibit histone deacetylases (from a low nanomolar range) and DNA methyltransferase-1 (from a mid-nanomolar range, IC50 < 200 nM).
Additionally, lysine methyltransferase G9a inhibitory activity is achieved (from a low nanomolar range) by introduction of a key lysine mimic group at the 7-position of the quinoline ring. The corresponding epigenetic functional cellular responses are observed: histone-3 acetylation, DNA hypomethylation, and decreased histone-3 methylation at lysine-9.
These chemical probes, multitarget epigenetic inhibitors, were validated against the multiple myeloma cell line MM1.S, demonstrating promising in vitro activity of 12a (CM-444) with GI50 of 32 nM, an adequate therapeutic window (>1 log unit), and a suitable pharmacokinetic profile. In vivo, 12a achieved significant antitumor efficacy in a xenograft mouse model of human multiple myeloma.